The epilepsies are a family of neurological disorders characterized by seizures, which are transient, recurrent perturbations of normal brain function. As a chronic condition, epilepsy affects about 1% of the population in the United States. This prevalence will increase substantially in the near future largely due to the rapidly expanding number of elderly Americans, in whom the incidence of epilepsy is the highest. Uncontrolled epilepsy poses a significant burden to society due to associated healthcare costs and chronic under-unemployment of otherwise physically and mentally competent individuals.
Anti-epileptic drug (AED) treatment is the standard therapy for epilepsy. Unfortunately, AEDs in current therapeutic use display significant side effect profiles. Additionally, about one third of all patients remain unresponsive to currently available medications. The need for more effective treatments for phamacoresistant epilepsy was among the driving forces behind a recent White House-initiated ‘Curing Epilepsy: Focus on the Future’ (‘Cure’) Conference (March, 2000), which emphasized specific research directions and benchmarks for the development of effective and safe treatments for people with epilepsy [3].
At the physiological level, seizure activity involves the transient, simultaneous hypersynchronous activation of a large population of neurons, either in one focal area, or throughout the brain, depending on the type of epilepsy. One of the more common forms of epilepsy in humans that is frequently resistant to current therapy is the mesial temporal lobe epilepsy syndrome, or limbic epilepsy, that originates from limbic structures such as the hippocampus and amygdala [4].
An alternative approach to controlling epilepsy with drugs is through the use of neuroprosthetic devices. For nearly thirty years, epileptologists have been studying macroscopic electroencephalographic (EEG) recordings from the scalp to obtain global and local measures of scalp potentials using a variety of linear, nonlinear, and dynamical computational measures [13-17]. On the surface of the cortex, ECoG grid electrodes have been used in the clinical setting to determine epileptic foci. In this approach, the analysis of the signals is conducted on a gross scale, that is at a system and circuit mechanism level, not at the cellular level [18, 19].
In studies performed in vitro using recent advances in multi-site electrode technology, acute preparations of hippocampal recordings have generated the basic constructs of neuronal firing related to the epileptic condition [20]. In conjunction with in vivo recordings in both humans and animals, “slice physiologists” have performed elegant experiments to infer the normal and bursting responses of single units in excised tissue [21]. It is recognized that such recordings from acute and slice preparations have provided significant contributions to research in the epilepsy field; however they are limited by the loss of network input and output from the rest of the brain (slice), and inability to chronically spontaneously seize, as do human subjects with temporal lobe epilepsy.
Several neuroprosthetic systems to treat epilepsy are presently available. The only existing seizure control system to have received FDA approval is based on electrical stimulation of the vagus nerve. The system is marketed by Cyberonics, Inc. (Houston, Tex.). Another system, developed by Neuropace (Mountain View, Calif.) delivers electrical stimulation to the brain by way of subdural strips upon detection of a electrical signals that occur at the start of a seizure.
Despite these advances, effective neuroprosthetics capable of predicting or warning of impending seizures and delivering timely therapeutic intervention have not been developed. The hallmark of epilepsy is recurrent seizures that are unpredictable and debilitating. Methods of seizure prediction in real-time would have significant impact on patients' lives. Even a few minutes of warning would allow a person experiencing a seizure to stop driving or get out of a risky environment to seek safety. Efforts in this area been limited by a lack of electrophysiologic control parameters that can be used to accurately predict the onset of the epileptic state and to deliver therapeutic feedback to the affected neural structures. In currently available systems, overall patterns of neuronal activity associated with the onset of seizure are detected, and upon such detection, standardized therapy is delivered to the brain in the form of electrical stimulation. The delivered stimulation is of pre-determined strength and duration, regardless of the strength or duration of the seizure. This lack of control results in delivery of an electrical stimulus that may either be insufficient or excessive, both with respect to duration and stimulus strength.
To predict and effectively treat an epileptic seizure, a “closed-loop” system is needed in which sensitive physiological parameters associated with an oncoming epileptic episode are used to detect the preictal state that precedes a seizure. Upon such detection, a stimulus of strength and duration appropriate to control the seizure would be delivered. Development of such devices for seizure prediction and treatment for epilepsy and related disorders would greatly improve the lives of many patients and yield considerable social benefits.